3444
Ojima et a].
J . Org. Chem., Vol. 43, No. 18, 1978
of ergosterol gives dihydrotachysterol? (DHTp). Structure 6a is that of dihydrotachysterol3(DHT3). (5) R. M. Wing, W. H. Okamura, M. R. Pirio, S. M. Sine, and A. W. Norman, Science, 186,939 (1974). (6)W. H. Okamura, M. L. Hammond, A. Rego, A. W. Norman, and R. M. Wing, J. Org. Chem., 42,2284 (1977). (7)C. W. Spangler, Chem Rev., 76,187 (1976). (8)J. A. Hirsch. "Concepts in Theoretical Organic Chemistry", Allyn and Bacon, Boston, 1974,p 253. (9) E. Havinga, Experientia, 29, 1181 (1973). (10)K. H. Hanewald, M. P. Rappoldt, and J. R. Roborgh. Red. Trav. Chim. Pays-Bas, 80, 1003 (1961). (11) J. L. M. A. Schlatmann, J. Pot, and E. Havinga, Red. Trav. Chim. Pays-@as,
83, 1173 (1964). (12)M. Akhtar and C. J. Gibbons, Tetrahedron Len., 9,509 (1965). (13)T. K. Murray, K. C. Day, and E. Kodicek, Biochem. J., 98,293(1966).The authors assumed the product to be isovitamin D3. However, the reaction conditions (sbC13 in CHCl3, 25 OC) lead exclusively to isotachysterol3: X, (EtOH) 279 (e 27 loo),289 (33600),301 nm (24600);NMR (CDCl3) 6 6.55 and6.40(AB,J=16Hz,2H,C6,7),3.98(m,1H,C3),1.79(s,3H,C19),
0.95(d, J = 6 HZ, 3 H, C-21),0.89(S,3 H, C-18), 0.86 (d, J = 6 Hz, 6 H, C2627);d e (re1 intensity) 384 (M', loo),369 (20),271 (45),259 (4),253 (20)-217 (18),199 (16),85 (35);75% yield from 2. (14) Isomerization of vitamin D trienes under GC conditions is a common observation. GC of 3 (2mm X 2 m glass column packed with 3% OV-101 on Chromosorb 30 100/120mesh; nitrogan flow rate 30 mllmin; oven held isothermally at 260 OC) gave two peaks with retention times of 3.2and 8.0 min. Interestingly, GC of either 5a or 5b gave the same trace as found for 3. In all three traces, the ratio of peak heights of the 3.2to the 8.0min peak was about 2.511.GC-MS of 3 showed that both peaks were isomers of nominal parent mass 384.The early peak showed m l e (re1 intensity) 384 (M', 18),351 (36),309 (41),283 (39,145 (33,124 (32).43 (100).The late peak gave 384 (M', 47).369 (20),271 (48),253 (42),199 (35),81 (85), 43 (100). (15)A minor component at h = 6.7min was also found in this sample; its parent ion at m l e 110 and fragmentation pattern suggest that it is methylcyclohexenone, the dehydration product of 7b.
(16)S.H. Maron and C. F. Prutton, "Principles of Physical Chemistry", Macmillan, Toronto, 1970,pp 569-570. (17)W. W. Cleland, Adv. Enzymol. Relat. Subj. Biochem., 29, 1 (1967).
Effective Biomimetic Route to D( +)-Pantothenate Using Asymmetric Hydrogenation Catalyzed by a Chiral Rhodium Complex in the Key Step Iwao Ojima,* Tetsuo Kogure, and Toshinaga Terasaki Sagami Chemical Research Center, N i s h i - O h n u m a 4-4-1, Sagamihara, Kanagawa 229, J a p a n
Kazuo Achiwa F a c u l t y of P h a r m a c e u t i c a l Sciences, U n i v e r s i t y of Tokyo, B u n k y o - k u , T o k y o 113, J a p a n Received F e b r u a r y 23, 1978 Asymmet,ric synthesis o f D(+)-pantothenate f r o m ketopantoyl lactone following a biomimetic route using asymm e t r i c hydrogenation in t h e k e y step is described. T h e asymmetric hydrogenation o f ketopantoyl lactone was effect i v e l y catalyzed by a r h o d i u m complex w i t h BPPM as c h i r a l ligand t o a f f o r d D(-)-pantoy1 lactone w i t h 86.7% o p t i cal purity under o p t i m u m conditions. T h i s was f u r t h e r recrystallized t o give t h e pure lactone in good yield. T h e p u r e D(-)-pantoy1 lactone thus obtained was converted t o e t h y l D(+)-pantothenate by reacting w i t h p-alanine e t h y l ester.
Pantothenic acid is a member of the B complex vitamins and is an important constituent of Coenzyme A. Pantothenic acid is converted t o pantetheine, which further reacts with adenosine triphosphate (ATP) to form Coenzyme A. The biosynthesis of pantothenic acid from valine has been postulated to involve1V2 (a) the oxidative deamination of valine to a-ketoisovaleric acid, (b) the hydroxymethylation of this acid to form ketopantoyl lactone, ( c ) the asymmetric reduction of ketopantoyl lactone to pantoyl lactone, and (d) the coupling of pantoyl lactone with @-alanineto give pantothenic acid Scheme I >CHCOOH
>COCOOH
I
" .
HCHO +
b
H
O
X
COCOOH
---
HO 0
0 H,NCH,CH,COOH d
OH a Transaminase. b K e t o p a n t o a l d o l a s e . d Pantothenate synthetase.
C
Reductase,
(Scheme I). Among these processes, step c is the most significant since only D( +)-pantothenic acid derived from D( -)pantoyl lactone has biological a ~ t i v i t y Although .~ the biological synthesis of D(+)-pantothenic acid has been reported using microbial reduction of ketopantoyl lactone to pantoyl l a ~ t o n e ,no ~ attempts have been made on the chemical asymmetric synthesis of this substance following the biosynthetic route. We have found that a rhodium complex with a chiral pyrrolidinodiphosphine, (2S,4S)-N-tert- butoxycar-
bonyl-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine (BPPM),5displays a high chiral recognition ability comparable to that of microorganisms, and thus the chiral rhodium complex can be considered as a functional biomimetic model of the ketopantoyl lactone reductase. We wish to present here a n effective biomimetic route to D(+)-pantothenic acid using a catalytic asymmetric hydrogenation in the key step as an application of the successful hydrogenation of a-keto esters catalyzed by neutral rhodium complexes with phosphine ligands.6 One of the key compounds in the biosynthetic route is ketopantoyl lactone since the asymmetric reduction of this compound is the characteristic process in biological systems. This eliminates the need for the optical resolution of racemic pantoyl lactone as employed in the commercial synthesis of D( +)-pantothenic acid derivatives.7 As the formation of ketopantoyl lactone is not restricted to enzymatic process but a simple aldol condensation, we started the asymmetric synthesis from ketopantoyl lactone.
0022-3263/78/1943-3444$01.00/00 1978 American Chemical Society
D ( + ) -Pantothenate
J . Org. Chem., Vol. 43, No. 18, 1978 3445
Table I. Asymmetric Hydrogenation of Ketopantoyl Lactone to D( -)-Pantoy1 Lactone Catalyzed by t h e BPPM-Rhodium (1\ Comolex
Solvent
Initial H2 pressure, atm
I3enzene Benzene Benzene Benzene THFe THFe THFe Chlorobenzene Toluene
50 50 50 50 50 50 50 50 50
Conversionb
[aIz5D,'
Conditionsa
%
deg
Optical purity,d % ee
10 "C, 48 h 20 "C, 48 h 30 "C, 48 h 50 "C, 24 h 0 "C, 70 h 15 "C, 48 h 30 "C, 48 h 50 "C, 48 h 50 "C, 48 h
95.4 99.2 100.0 100.0 46.1 69.7 99.5 94.5 99.6
-23.4 -43.4 -44.0 -43.0 -13.4 -41.9 -40.9 -32.2 -39.4
46.2 85.5 86.1 84.8 26.4 82.6 80.7 63.5 77.7
a A 0.99-1.06 mol % amount of the catalyst was employed; [BPPM]/[Rh] = 1.12-1.17. Determined by GLC analysis. As the reaction does not involve any side reactions at all, this value corresponds to the chemical yield. Measured in water; c = 2.010-2.098. d Optical purity was calculated on the basis of the maximum rotation of the pure enantiomer, [,Iz5, max -50.7" (c 2.05, HzO) (ref 3). e T H F = tetrahydrofuran.
The asymmetric hydrogenation of ketopantoyl lactone was carried out by means of a homogeneous rhodium complex having BPPM as t h e chiral ligand. This gave D(-)-panioyl lactone with an optical purity of 86.7% in almost quantitative yield under optimum conditiom8 T h e results obtained in the asymmetric hydrogenation under a variety of conditions are summarized in Table I. T h e corresponding asymmetric hydrogenation using (-)-DIOPg as t h e chiral ligand in tetrahydrofuran at 20 "C resulted in only a 35% enantiomeric excess. As Table I shows, (i) t h e optical yield is affected by t h e solvent employed, with benzene affording t h e best results as far as we have examined, and (ii) a remarkable effect of t h e reaction temperature on t h e optical yield is observed. It is of interest that t h e extent of asymmetric induction decreases precipitously a t temperatures below ca. 10 "C. This phenomenon could be caused by either (i) a change in t h e ratedetermining step or (ii) a n exchange of one mechanism for another, provided t h e reaction proceeds via two parallel mechanisms. A configurational change of the chiral ligand in the coordination sphere of the rhodium complex could be idso suggested. As to the direction of asymmetric induction, R configuraiion is found to be extremely favored, thus leading to the formation of the naturally occurring D(-p pantoy lactone which has been shown to have the R ~ o n f i g u r a t i o nThus, . ~ ~ the direciion of asymmetric induction realized in the present reaction is the same as that observed in t h e asymmetric hydrogenation of pyruvates using either (-)-DIOP or BPPM as the chiral ligand." T h e pantoyl lactone thus obtained was easily purified t o give the pure D isomer by recrystallization from n-hexanebenzene. Accordingly, a pure sample of D( -) -pantoy1 lactone was obtained in at least 70% yield from ketopantoyl lactone. T h e pure sample of D(-)-pantoy1 lactone was converted in 77% yield to t h e ethyl ester of D(+)-pantothenic acid by reacting with @-alanineethyl ester. The transformations of ethyl D( +)-pantothenate t o D( +)-pantothenic acid and t o pantetheine are known p r o c e s ~ e s . ~Synthesis J~ of calcium pantothenate from D( -) -pantoy1 lactone, @-alanine,and calci um metal or ions has been established.7 As t h e optical yield attained in a microbial reduction of ketopantoyl lactone using baker's yeast has been reporteld t o be ca. 72%,4our chiral rhodium catalyst is shown to be superior t o baker's yeast in this reaction. Although Lanzilotta e t al. recently have found that specific strains of a n ascomycete, Byssochlamys fulua, can achieve exceedingly high optical yield production of the D isomer: the isolation procedure from aqueous media, Le., extraction, recovery of raw materials, and purification, is very troublesome because of the high solubility
of t h e product in water. Thus, t h e present reaction has some advantages from a synthetic point of view; Le., (i) conversion of t h e reaction is virtually 10096, and (ii) t h e isolation of t h e product is quite simple and convenient since t h e reaction is carried out in small amounts of nonaqueous media. Further studies on achieving high stereoselectivity using a variety of chiral ligands are actively under way.
Experimental Section Measurements. Melting points and boiling points are uncorrected. The infrared spectra were measured on a Hitachi EPI-G3 spectrophotometer using samples as neat liquid or in KBr disks. The nuclear magnetic resonance spectra were obtained using a Varian XL-100, HA-100, or T-60 spectrometer with Me4Si as an internal standard. Analytical gas chromatography (GLC) was carried out on a Shimadzu GC-3BF using a column packed with 3% PEG-2OM. Materials. [Rh(cycloocta-1,5-diene)Cl]~ was prepared from rhodium trichloride trihydrate and ~ycloocta-1,5-diene.~~ BPPM was prepared from L-4-hydroxyplorine in accordance with a previously reported m e t h ~ dKetopantoyl .~ lactone was prepared by the oxidation of DL-pantoyl lactone with N-bromosuccinimide in 85% yield by a modified method of Broquet and Bedin.12The shift reagent for NMR measurements, tris[3-(trifluorornethylhydroxymethylene)-d-~amphorato]europium(III) [Eu(facam)a],was commercially available from Willow Brook Laboratories, Inc. Preparation of the Catalyst Solution. The optically active catalyst was prepared in situ by the reaction of [Rh(cycloocta-l,5diene)Cl]z with the chiral diphosphine in a degassed solvent at ambient temperature. In a typical experiment, 24.4 mg (4.95 X lod5mol) of [Rh(cycloocta-1,5-diene)Cl]~ and 60.0 mg (1.08 X mol) of BPPM were dissolved in 8 mL of benzene under an argon atmosphere and stirred for 15 min. Similarly, the (-)-DIOP-rhodium catalyst was prepared from 24.4 mg (4.95 X lo+' mol) of [Rh(cycloocta-1,5mol) of (-)-DIOP in 8 mL of diene)Cl]z and 53.8 mg (1.08 X benzene. Asymmetric Hydrogenation of Ketopantoyl Lactone. In a typical run, 1.28 g (10.0 mmol) of ketopantoyl lactone was added to 8 mL of a degassed benzene solution of BPPM-rhodium complex (1.08 X mmol, 1.08 mol%) in a autoclave under argon. After the argon atmosphere was displaced by hydrogen, the hydrogenation was carried out under an initial hydrogen pressure of 50 atm at 30 "C for 48 h with stirring. The GLC analysis of the reaction mixture revealed that the conversion of the reaction was 100%.The solvent was evaporzted, and the residue was distilled under reduced pressure to afford 1.21 g (93%) of pantoyl lactone: bp 92 " c (4 mmHg); [CtIz5D -44.0" (c 2.010, H20). An NMR (100 MHz) measurement using Eu(facam)Bshowed that the purity of the enantiomer thus obtained was 86% enantiomeric excess. The pantoyl lactone (1.21g) thus obtained was recrystallized from n-hexane-benzene (3:l) to afford 854 mg (70.6%)of pure D(-)-pantoy1 lactone, [CtIz5D -50.8 f 0.1" ( c 2.055, H20). When the conversion of the reaction was lower than 99%, the reaction mixture was submitted to column chromatography on silica. Then, pantoyl lactone was separated from unreacted ketopantoyl lactone and used for the measurement of optical rotation. Synthesis of Ethyl D(+)-Pantothenate. Ethyl D(+)-pantothenhte was synthesized by a modified method of Giissner et a l l 3 Pure
3446
J . Org. Chem., Vol. 43, No. 18, 1978
Jain, Tuli, and Gupta
D(-)-pantoy1 lactone (2.60 g, 20 mmol), obtained in the above reaction, was mixed with freshly distilled P-alanine ethyl ester (2.80 g, 24 mmol) in 20 mL of benzene and heated under reflux for 6 h. After the solvent was evaporated, the residue was submitted to column chromatography on silica. The unreacted pantoyl lactone was recovered (0.52 g, 20%) from the n-hexane-benzene eluate, and ethyl D(+)pantothenate (3.80 g, 77%) was obtained from the ether eluate. Ethyl ~ (c 2.18, absolute D(+)-pantothenate: colorless liquid; [ a ] l s+42.20’ EtOH). Anal. Calcd for CllH2105N: C, 53.43; H, 8.56; N, 5.66. Found: C, 53.39; H, 8.69; N, 5.47. The previously reported maximum rotation of this compound by Giissner et al. was [CY]’~Df36.8’ ( c 4.68, absolute EtOH). This lower value could be due to a partial racemization during distillation at high temperature. Acknowledgment. The authors are grateful to Dr. S. Iriuchijima of Sagami Chemical Research Center for his helpful discussions.
R e f e r e n c e s a n d Notes M. Purko, W. 0. Nelson, and W. A. Wood, J. Biol. Chem., 207, 51
(1954). G. M. Brown and J. J. Reynolds, Annu. Rev. Biochem., 32, 419 (1963). (a) E. T. Stiller, S.A. Harris, J. Finkelstein, J. C. Keresztesy,and K. Folkers, J. Am. Chem. Soc.. 62, 1785 (1940); (b) R. K. Hill and T. H. Chan, Biochem. Biophys. Res. Commun., 38, 181 (1970). R. P. Lanzilotta, D. G. Bradley, and K. M. McDonald, Appl. Microbiol., 27,
130 (1974). K. Achiwa, J. Am. Chem. Soc., 98,8265 (1976). I. Ojima, T. Kogure, and K. Achiwa, J. Chem. Soc., Chem. Commun., 428
(1977). E.g., F. Kagan, R. V. Heinzelman, D. I. Weisblat, and W. Greiner, J. Am. Chem. Soc., 79, 3545 (1957),and references therein: U.S. Patent 2 780 645,1957:US. Patent 2 845 456,1958. As to the preliminary results, see K. Achiwa. T. Kogure, and i. Ojima, Tetrahedron Lett., 4431 (1977). DlOP stands for 2,3-Oisopropylidene-2,3dihydroxy-1,4-bls(diphenylphosphin0)butane: H. 6.Kagan and T.-P. Dang, J. Am. Chem. SOC.,94,
6429 (1972). E. L. Wittle, J. A. Moore, R . W. Stipek, F. E. Peterson, V. M. McGlohon, 0. D. Bird, G. M. Brown, and E. E. Snell, J. Am. Chem. SOC., 75, 1694
(1953).
Registry No.-Ethyl D(+)-pantothenate, 10527-68-1; BPPM, 61478-28-2; [Rh(cycloocta-1,5-diene)Cl]z,12092-47-6; ketopantoyl lactone, 13031-04-4;D(-p pantoy lactone, 599-04-2; BPPM-rhodium(1) complex, 66787..44-8;ethyl p-alaninate, 924-73-2.
J. Chatt and L. M. Venanzi, J. Chem. SOC.,4735 (1957).
C.Broquet and J. Bedin, C. R. Hebd. Seances Acad. Sci., Ser. C, 262, 1891 (1966). A. Gijssner, M. GBtzi-Fichter, and T. Reichstein, Helv. Chim. Acta, 23, 1276
(1940).
Synthesis of Pomiferin, Auriculasin, and Related Compounds Amolak C. Jain,* Deepak K. Tuli, and Ramesh C. Gupta Department of Chemistry, Himachal Pradesh University, Summer Hill, Simla 171 005, India Received December 21,1977
Nuclear prenylation of 3’,4’-di-O-methylorobo1(4) with prenyl bromide under alkaline conditions has yielded its 7-0-prenyl (8), 6-C-prenyl (12),and 6,8-di-C,C-prenyl (9) derivatives. Acetylation, partial methylation, and cyclization with formic acid of 12 and 9 separately and their NMR spectra established their structures. Cyclodehydrogenation of 9 with DDQ gave di-0-methyl derivatives (6 and 18) of pomiferin and auriculasin, respectively. Pomiferin (1)and auriculasin (5)themselves were synthesized by nuclear prenylation of orobol(19), giving the 6-C-prenyl(21) and the 6,8-di-C,C-prenyl (20)derivatives. Cyclodehydrogenation of 6,8-di-C,C-prenylorobol (20)afforded both the isomers (1 and 5). Cyclodehydrogenations of 21 and 12 yielded 6”,6”-dimethylpyrano[2”,3”:7,6]orobol(22) and its dimethyl ether (16),respectively. Pomiferin was isolated from the fruit of the osaje orange tree, Maclura pornift?ra Raf., along with osajin (Dr. D. Dreyer, Western Regional Research Laboratory, Berkeley, states that both osajin and pomiferin are present in almost equal amounts in the fruit), and assigned the structure of 5,3’4’-trihydroxy - 6 - C - prenyl-6”,6“-dimethylpyrano[2”,3”:7,8]isoflavone (1) by Wolfrom et a1.1,2 using mostly the chemical 2, R = H (dihydroisopomiferin) 11. R = Me
OR ;l,R = H (pomiferin)
6. R
=
3
synthesized 2 from 3’,4’-di-O-methylorobo1(4) by reacting it with prenyl bromide in the presence of zinc chloride and benzene. Auriculasin recently isolated from Milletia auriculata (Leguminosae) has been assigned the isomeric structure 5 by Minhaj et aL4 on the basis of its special data and those on its trimethyl ether and triacetate. We now report the synthesis
Me
methods of degradation and color reactions. The only synthetic evidence given so far has been the synthesis of its derivative, dihydroisopomiferin (2), formed in two stages. Wolfrom et a1.2 synthesized dihydroisopomiferin (2) from bis(dihydropyrano)phloroglucinol(3) by Hoesch reaction with 3,4-dimethoxybenzyl cyanide, followed successively by isoflavone condensation with ethyl formate in the presence of sodium and demethylation with HI, whereas Raizada e t aL3
0022-3263/78/1943-3446$01.00/00 1978 American Chemical
4 , R = Me 19,R = H Socict;,
